Integrated omics profiling and network pharmacology uncovers the prognostic genes and multi-targeted therapeutic bioactives to combat lung cancer.

Non-small cell lung cancer (NSCLC) is the frequent subtype of lung cancer and the currently used treatment methods, diagnosis, and chemoresistance are relatively ineffective. Determining the pharmacological targets from active biomolecules of medicinal plants has become a frontiers era for biomedical research to develop novel therapies. In view of these scenarios, this pilot study, network pharmacology, cheminformatics, integrative omics, molecular docking and in vitro anti-cancer analysis were performed to unveil the multi-targeted treatment mechanisms of novel plant bioactives to treat lung cancer. Bioactive molecules from medicinal plants were compiled from PubChem. Network pharmacology approach revealed that 29 compounds efficiently target the 390 human and lung cancer associated genes. In addition, comparative analysis was performed and identified the 7 bioactive molecules significantly targeting 8 lung cancer genes. The integrative omics analysis discovered unique genes between the lung cancer and normal lung tissues. These genes were further validated through protein-protein interaction, gene ontology, gene functional and pathway enrichment, boxplot and overall survival analyses to understand the function of unique genes and their involvement in cancer signaling pathways. Survival heatmap analyses identified the significant prognostic genes. Docking results revealed that, lupeol and p-coumaric acid displayed high binding affinities with MIF, CCNB1, FABP4. Hence, we selected these two bioactives for in vitro analysis. Furthermore, these selected bioactives were showed concentration dependent cytotoxicity against the lung adenocarcinoma cells (A549). This holistic study has opened up novel avenues and unravels the cancer prognostic genes which could serve as druggable target and bioactives with anti-cancerous efficacy. Further functional validations are prerequisites to deciphering these bioactives as commercial drug candidates.

Top-down, bottom-up, and history-driven processing of multisensory attentional cues in intellectual disability: An experimental study in virtual reality.

Models of attention demonstrated the existence of top-down, bottom-up, and history-driven attentional mechanisms, controlled by partially segregated networks of brain areas. However, few studies have examined the specific deficits in those attentional mechanisms in intellectual disability within the same experimental setting. The aim of the current study was to specify the attentional deficits in intellectual disability in top-down, bottom-up, and history-driven processing of multisensory stimuli, and gain insight into effective attentional cues that could be utilized in cognitive training programs for intellectual disability. The performance of adults with mild to moderate intellectual disability (n = 20) was compared with that of typically developing controls (n = 20) in a virtual reality visual search task. The type of a spatial cue that could aid search performance was manipulated to be either endogenous or exogenous in different sensory modalities (visual, auditory, tactile). The results identified that attentional deficits in intellectual disability are overall more pronounced in top-down rather than in bottom-up processing, but with different magnitudes across cue types: The auditory or tactile endogenous cues were much less effective than the visual endogenous cue in the intellectual disability group. Moreover, the history-driven processing in intellectual disability was altered, such that a reversed priming effect was observed for immediate repetitions of the same cue type. These results suggest that the impact of intellectual disability on attentional processing is specific to attentional mechanisms and cue types, which has theoretical as well as practical implications for developing effective cognitive training programs for the target population.

Anti-Inflammatory Activity of Lobaric Acid via Suppressing NF-κB/MAPK Pathways or NLRP3 Inflammasome Activation.

Lobaric acid (LA) is a constituent of the lichen Stereocaulon alpinum. LA has multiple biological activities, including antibacterial and antioxidant ones. The purpose of this study was to investigate the effect of LA and its mechanism on lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Macrophages were pretreated with different concentrations of LA (0.2 - 20 µM), followed by LPS stimulation. LA treatment of LPS stimulated macrophages decreased their nitric oxide production and the expression of cyclooxygenase-2 and prostaglandin E2. LA also significantly reduced the production of tumor necrosis factor-α and interleukin (IL)-6 by inhibiting the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB). Additionally, LA inhibited the production of IL-1ß and IL-18, as well as caspase-1 maturation, by inhibition of NLRP3 inflammasome activation in LPS/ATP-stimulated cells. These results strongly suggest that LA could inhibit inflammation by downregulating NF-κB/MAPK pathways and NLRP3 inflammasome activation in activated macrophages. These results reveal a new therapeutic approach to modulate inflammatory diseases linked to deregulated inflammasome activities.

Comparison of Combined Therapy Using Conventional Chemoembolization and Radiofrequency Ablation Versus Conventional Chemoembolization for Ultrasound-Invisible Early-Stage Hepatocellular Carcinoma (Barcelona Clinic Liver Cancer Stage 0 or A).

Objective: To compare the therapeutic efficacy between conventional transarterial chemoembolization (cTACE) and combined therapy using cTACE and radiofrequency ablation (RFA) in ultrasound (US)-invisible early stage hepatocellular carcinoma (HCC). Materials and Methods: From January 2008 to June 2016, 167 patients with US-invisible early stage HCCs were treated with cTACE alone (cTACE group; n = 85) or cTACE followed by immediate fluoroscopy-guided RFA targeting intratumoral iodized oil retention (combined group; n = 82). Procedure-related complications, local tumor progression (LTP), time to progression (TTP), and overall survival (OS) were compared between the two groups. Multivariate analyses were performed to identify prognostic factors. Results: There was no major complication in either group. The cTACE group showed higher 1-, 3-, and 5-year LTP rates than the combined group; i.e., 12.5%, 31.7%, and 37.0%, respectively, in the cTACE group; compared to 7.3%, 16.5%, and 16.5%, respectively, in the combined group; p = 0.013. The median TTP was 18 months in the cTACE group and 24 months in the combined group (p = 0.037). Cumulative 1-, 3-, and 5-year OS rates were 100%, 93.2%, and 87.7%, respectively, in the cTACE group and 100%, 96.6%, and 87.4%, respectively, in the combined group (p = 0.686). Tumor diameter > 20 mm and cTACE monotherapy were independent risk factors for LTP and TTP. Conclusion: Combined therapy using cTACE followed by fluoroscopy-guided RFA is a safe and effective treatment in US-invisible early stage HCCs. It provides less LTP and longer TTP than cTACE alone.

Diagnostic Performance of Alpha-Fetoprotein, Protein Induced by Vitamin K Absence, Osteopontin, Dickkopf-1 and Its Combinations for Hepatocellular Carcinoma.

BACKGROUND & AIMS: Alpha-fetoprotein (AFP) is the most widely used serum biomarker for hepatocellular carcinoma (HCC), despite its limitations. As complementary biomarkers, protein induced by vitamin K absence (PIVKA-II), osteopontin (OPN), and Dickkopf-1 (DKK-1) have been proposed. This study aimed to perform a head-to-head comparison of the diagnostic performance of AFP, PIVKA-II, OPN and DKK-1 as single or in combination to seek the best biomarker or panel, and to investigate the clinical factors affecting their performance. METHODS: Using 401 stored plasma samples obtained from 208 HCC patients and 193 liver cirrhosis control patients, plasma AFP, PIVKA-II, OPN and DKK-1 levels were measured by ELISA, and receiver operating characteristic curve analyses were performed for each biomarker and for every combination of two to four markers. RESULTS: Of the four biomarkers, AFP showed the highest area under the curve (0.786). The sensitivity and specificity for each single biomarker was 62% and 90.2% (AFP>20 ng/mL), 51.0% and 91.2% (PIVKA-II>10 ng/mL), 46.2% and 80.3% (OPN>100 ng/mL), and 50.0% and 80.8% (DKK-1>500 pg/mL), respectively. Among the combinations of two biomarkers, AFP>20 ng/mL or DKK-1>500 pg/mL showed the best diagnostic performance (sensitivity 78.4%, specificity 72.5%). Triple or quadruple combination did not improve the diagnostic performance further. The patient's age, etiology and tumor invasiveness of HCC affected the performance of each marker. CONCLUSIONS: AFP was the most useful single biomarker for HCC diagnosis, and the combined measurement of AFP and DKK-1 could maximize the diagnostic yield. Clinical decision should be based on the consideration of various factors affecting the diagnostic performance of each biomarker. Efforts to seek novel HCC biomarkers should be continued.

Effects of N-acetylcysteine on First-Line Sequential Therapy for Helicobacter pylori Infection: A Randomized Controlled Pilot Trial.

BACKGROUND/AIMS: To evaluate the adjuvant effects of N-acetylcysteine (NAC) on first-line sequential therapy (SQT) for Helicobacter pylori infection. METHODS: Patients with H. pylori infections were randomly assigned to receive sequential therapy with (SQT+NAC group, n=49) or without (SQT-only group, n=50) NAC. Sequential therapy consisted of rabeprazole 20 mg and amoxicillin 1 g for the first 5 days, followed by rabeprazole 20 mg, clarithromycin 500 mg and metronidazole 500 mg for the remaining 5 days; all drugs were administered twice daily. For the SQT+NAC group, NAC 400 mg bid was added for the first 5 days of sequential therapy. H. pylori eradication was evaluated 4 weeks after the completion of therapy. RESULTS: The eradication rates by intention-to-treat analysis were 58.0% in the SQT-only group and 67.3% in the SQT+NAC group (p=0.336). The eradication rates by per-protocol analysis were 70.0% in the SQT-only group and 80.5% in the SQT+NAC group (p=0.274). Compliance was very good in both groups (SQT only/SQT+NAC groups: 95.2%/100%, p=0.494). There was no significant difference in the adverse event rates between groups (SQT-only/SQT+NAC groups: 26.2%/26.8%, p=0.947). CONCLUSIONS: The H. pylorieradication rate was numerically higher in the SQT+NAC group than in the SQT-only group. As our data did not reach statistical significance, larger trials are warranted.

The effect of coffee consumption on the development of hepatocellular carcinoma in hepatitis B virus endemic area.

BACKGROUND & AIMS: Coffee consumption is inversely related to the risk of cirrhosis or hepatocellular carcinoma (HCC). However, the protective effect of coffee drinking against the risk of HCC was not established in HBV-prevalent region. To elucidate the relationship between lifetime coffee consumption and the risk of HCC development under the consideration of replication status of HBV. METHODS: A hospital-based case-control study was performed in 1364 subjects. A total of 258 HCC patients, 480 health-check examinees (control 1, HCE) and 626 patients with chronic liver disease other than HCC (control 2, CLD) were interviewed on smoking, alcohol and coffee drinking using a standardized questionnaire. HBV e-antigen (HBeAg) status and serum HBV DNA levels were measured in patients infected with HBV. RESULTS: After adjustment for age, gender, obesity, DM, presence of hepatitis virus (except for HCE) and lifetime alcohol drinking/smoking, a high lifetime coffee consumption (≥20 000 cups) was an independent protective factor against HCC, in each analyses using healthy and risky control groups respectively (HCE group, OR 0.56, 95% CI 0.33-0.95; CLD group, OR 0.55, 95% CI 0.36-0.85). However, the high coffee consumption did not affect the HCC risk in patients with HBV (OR 0.64, 95% CI 0.36-1.14) after adjustment for HBeAg status, serum HBV DNA level and antiviral therapy. CONCLUSIONS: A high lifetime coffee consumption was negatively associated with a HCC development. However, this difference of coffee exposure with the HCC group was reduced in chronic hepatitis B patients by the dominant role of viral replication.

Effects of coffee, smoking, and alcohol on liver function tests: a comprehensive cross-sectional study.

BACKGROUND: Liver function tests (LFTs) can be affected by many factors and the proposed effects of coffee on LFT require a comprehensive evaluation. The aim of this study was to elucidate whether drinking coffee, smoking, or drinking alcohol have independent effects on LFTs in Korean health-check examinees. METHODS: We used the responses of 500 health-check examinees, who had participated in a self-administered questionnaire survey about coffee, alcohol drinking, and smoking habits. RESULTS: Coffee consumption was closely related to male gender, high body mass index (BMI), alcohol drinking, and smoking. On univariable and multivariable analyses, drinking coffee lowered serum levels of total protein, albumin, and aspartate aminotransferases (AST). On multivariable analyses, smoking raised serum γ-glutamyl transferase (GGT) level and decreased serum protein and albumin levels, while alcohol drinking raised GGT level after adjustment for age, gender, regular medication, BMI, coffee and alcohol drinking amounts, and smoking. CONCLUSIONS: Coffee consumption, smoking, and alcohol drinking affect the individual components of LFT in different ways, and the above 3 habits each have an impact on LFTs. Therefore, their effects on LFTs should be carefully interpreted, and further study on the mechanism of the effects is warranted.

Fermented rice bran downregulates MITF expression and leads to inhibition of alpha-MSH-induced melanogenesis in B16F1 melanoma.

Rice bran contains various polyphenolic compounds with anti-oxidative activities, and it has long been known to inhibit melanogenesis, but the inhibition mechanism has not been fully elucidated. Cofermentation of rice bran with Lactobacillus rhamnosus and Saccharomyces cerevisiae significantly reduced the cytotoxicity of the resulting extract to B16F1 melanoma cells. Marked reduction of alpha-melanocyte stimulating hormone (MSH) induced melanin synthesis was also observed upon treatment with fermented rice bran extract but it had no direct inhibitory effect on tyrosinase activity, while the intracellular tyrosinase activity was reduced by the extract. This result was further confirmed by an immunoblot assay measuring the level of tyrosinase protein. In addition, the expression of microphthalmia-associated transcription factor (MITF), a key regulator of melanogenesis, was significantly decreased by the extract. All together, the fermented rice bran extracts showed an inhibitory effect on melanogenesis through downregulation of MITF, along with reduced cytotoxicity.

Suppression of mast cell degranulation by a novel ceramide kinase inhibitor, the F-12509A olefin isomer K1.

Antigen-induced degranulation of mast cells plays a pivotal role in allergic and inflammatory responses. Recently, ceramide kinase (CERK) and its phosphorylated product ceramide 1-phosphate (C1P) have emerged as important players in mast cell degranulation. Here, we describe the synthesis of a novel F-12509A olefin isomer, K1, as an effective CERK inhibitor. In vitro kinase assays demonstrated that K1 effectively inhibits CERK without inhibiting sphingosine kinase and diacylglycerol kinase. Treating RBL-2H3 cells with K1 reduced cellular C1P levels to 40% yet had no effect on cell growth. Furthermore, treatment with K1 significantly suppressed both calcium ionophore- and IgE/antigen-induced degranulation, indicating that K1 interferes with signals that happen downstream of Ca(2+) mobilization. Finally, we show that K1 affects neither IgE/antigen-induced global tyrosine phosphorylation nor subsequent Ca(2+) elevation, suggesting a specificity for CERK-mediated signals. Our novel CERK inhibitor provides a useful tool for studying the biological functions of CERK and C1P. Moreover, to our knowledge, this is the first report demonstrating that inhibition of CERK suppresses IgE/antigen-induced mast cell degranulation. This finding suggests that CERK inhibitors might be a potential therapeutic tool in the treatment of allergic diseases.

[Trial of moxifloxacin-containing triple therapy after initial and second-line treatment failures for Helicobacter pylori infection].

BACKGROUND/AIMS: Proton-pump inhibitor (PPI)-based triple therapy for Helicobacter pylori eradication is widely used with considerable failure rate. Bismuth-based, second-line therapy is also associated with failures in more than 20% of cases in Korea. Our aim was to evaluate the efficacy and tolerability of third-line therapy containing moxifloxacin as a rescue in Korea. METHODS: The subjects consisted of 201 patients infected with H. pylori, who were treated with PPI-based therapy, 42 patients treated with bismuth-based after failure of initial PPI triple therapy, and 10 patients treated with moxifloxacin-containing triple therapy after failure of successive initial and second-line therapy. Eradication rate, compliance and side effect rates were compared. RESULTS: The eradication rates of initial, second-line, and third-line therapy were as follows: 67.2%/83.3%, 54.8%/76.7%, 80.0%/88.9% by intention-to-treat and per protocol analysis, respectively. The compliance of patients for each treatment was 98.2%, 90.9%, 100%, respectively. The side effect rate was significantly higher in the bismuth triple therapy than in the PPI- or moxifloxacin-containing triple therapy (p<0.05). CONCLUSIONS: Moxifloxacin-containing triple therapy shows high eradication rate with fewer side effects and good compliance. Thus, this regimen could be used as a rescue therapy.